臺灣博碩士論文加值系統

Paclitaxel是一種microtubule-active agent，它會與β-tublin結合，穩定microtubule之結構改變其動態不平衡狀態，造成細胞停滯在G2/M phase，最後走向細胞凋亡。Paclitaxel刺激後會活化JNK/SAPK (c-Jun N-terminal kinases/stress-activated protein kinases)，隨後磷酸化c-Jun，c-Jun為一transcription factor，活化後會啟動下游基因之表現。有研究發現JNK之活化為paclitaxel啟動細胞凋亡前期所必須；然而，JNK確切之角色仍不清楚，以及哪些下游基因受其調控仍所知甚少。我以SP600125抑制JNK磷酸化c-Jun，雖然SP600125對細胞之毒性很低，但發現在較高濃度時〈20 μΜ以上〉會造成細胞停滯在G2/M phase；以SP600125前處理一小時後再加入paclitaxel能抑制c-Jun之磷酸化，也能抑制細胞的死亡。本實驗使用cDNA microarrays之技術篩選JNK下游之調控基因；共篩選出20個基因，其中14個基因在paclitaxel刺激後轉錄增加，而在SP600125處理後被抑制；另外6個基因則反之。大部分之基因參與了cytoskeleton結構調節、細胞之生長、細胞凋亡，以及其他訊息傳遞路徑。而其確切的功能與在paclitaxel刺激引起之細胞凋亡中所扮演的角色則有待進一步的研究與探討。

Paclitaxel is one of the microtubule-active agents. It interacts with β-tubulin, stabilzes the microtubule structure and thus alters the microtubule dynamics, resulting in the G2/M phase arrest. After a prolonged G2/M arrest, cells undergo apoptosis. Paclitaxel also activates JNK/SAPK (c-Jun N-terminal kinases/stress-activated protein kinases) and the activated JNK further phosphorylates c-Jun, a transcription factor, regulating downstream genes expression. JNK activation is required for the early phase of paclitaxel-induced apoptosis. However, the exact role of JNK in paclitaxel-induced apoptosis is not completely clear, and genes that are involved in paclitaxel-induced apoptosis remain to be clarified. SP600125, a JNK inhibitor, can inhibit the phosphorylation of c-Jun by JNK. Although the cytotoxicity of SP600125 was low, we found that, at high concentration of SP600125, cells arrest at the G2/M phase. Pretreatment of SP600125 inhibited the activation of c-Jun and reduced the paclitaxel-induced apoptosis. Using cDNA microarrays, I also analyzed the downstream target genes of c-Jun upon JNK activation. Twenty genes were selected and 14 among them were upregulated by paclitaxel and could be downregulated by SP600125; and the other 6 were downregulated by paclitaxel and could be upregulated by SP600125. Most of the genes were involved in the regulation of cytoskeleton, cell growth, apoptosis and other signal transduction pathways. Results of my study have detected some interesting genes that are worth further studies
to characterize their roles in paclitaxel-induced apoptosis.

第一章、序論
第一節 細胞週期
〈一〉細胞週期的調控………………………………………………..1
〈二〉G1 phase與G1-S checkpoint………………………………….2
〈三〉G2 phase, G2/M transition與G2 checkpoint………………….3
第二節 細胞凋亡
〈一〉death-receptor-induced extrinsic pathway………………………5
〈二〉mitochondria-apoptosome-mediated apoptotic intrinsic pathway………………………………………………………...6
第三節 Microtubule-active agents — Paclitaxel……………………...…7
〈一〉Paclitaxel-induced apoptosis的路徑……………………………9
〈二〉低濃度與高濃度下Paclitaxel的作用…………………………11
〈三〉c-Jun NH2-terminal kinase (JNK)在paclitaxel-induced apoptosis
的角色…………………………………………………………12
第四節 c-Jun NH2-terminal kinase (JNK)
〈一〉JNK pathway…………………………………………………….13
〈二〉JNK與細胞凋亡………………………………………………..15
〈三〉c-Jun的生物功能……….………………………………………15
第五節 c-Jun NH2-terminal kinase (JNK) pathway之抑制………….18
第二章、實驗材料與方法
一、細胞培養…………………………………………………………22
二、Cell growth and cell death assay…………………………………22
三、免疫螢光染色法〈Immunofluorescent staining〉………………23
四、西方點墨法〈Western blotting〉………………………………..24
五、流式細胞儀分析〈Flow cytometry〉……………………………25
六、RNA extraction…………………………………………………..26
七、cDNA Microarraying………….…………………………………27
八、cDNA preparation from RNA……………………………………28
九、Real-time Polymerase Chain Reaction…………………………28
十、數據分析…………………………………………………………28
第三章、實驗結果
一、 Toxicity of Taxol to BR cells……………………………30
二、Microtubule changes after Paclitaxel treatment………… 30
三、Paclitaxel treatment induced apoptosis in BR cell………31
四、Paclitaxel induced JNK activation in BR cells………………31
五、JNK inhibitor ( SP600125 ) inhibit Paclitaxel induced JNK activation………………………………………………………32
六、Toxicity of SP600125 to BR cells………………………………32
七、Effect of SP600125 on the cell cycle…………………………33
八、SP600125 inhibited paclitaxel-induced apoptosis……………33
九、在paclitaxel作用下，SP600125透過JNK對基因轉錄之影響..33
十、Real-Time RT-PCR……………………………………………….35
第四章、討論……………………………………………………………37
第五章、結論……………………………………………………………46
參考文獻………………………………………………………………..47
圖表……………………………………………………………………..53

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